Mechanisms of cell contact inhibition and their dysregulation in cancer.

描述(申请人提供)：正常细胞在条件不合适时具有抑制增殖的机制，而肿瘤细胞绕过这些机制继续增殖。当细胞达到临界数量和密度时，这些调节机制由不同的刺激触发，如细胞-细胞接触。这种“接触抑制”在肿瘤形成过程中变得失调，我们的长期目标是确定和描述细胞接触如何触发抗增殖/生长控制信号的机制。在这些信号的调控中起核心作用的是Merlin，它是NF2(神经纤维瘤病2型)肿瘤抑制基因的蛋白质产物。最近的研究表明，NF2等位基因在广泛的肿瘤中处于功能失活状态。Merlin定位于细胞与细胞接触的区域，Merlin功能丧失的一个主要表现是体内肿瘤的发展和对细胞增殖的“接触抑制”的丧失。Merlin已被证明是多种信号转导途径的关键调节者，包括那些由小G蛋白和Hpo/Yap途径调节的信号转导途径。虽然这些通路在细胞增殖、器官大小控制和组织修复中起着关键作用，但目前还不清楚哪些通路介导了Merlin的肿瘤抑制功能/S。我们最近发现，Motin蛋白家族的成员Angiomotins是Merlin相互作用的蛋白质，定位于紧密连接和粘连连接。重要的是，我们确定了Merlin调节有丝分裂信号的能力是通过Angiomotins介导的，并且Angiomotins是NF2动物模型中肿瘤发生所必需的。我们的工作假设是，Merlin通过调节信号通路发挥肿瘤抑制作用，该信号通路通过与Angiomotins的相互作用控制细胞的增殖，而靶向Angiomotins将导致抑制肿瘤的发生。我们将使用NF2的细胞模型和动物模型来验证这些假说，以确定Merlin和Angiomotin依赖的细胞增殖调控机制，建立Hpo/YAP通路和Angiomotin在NF2中的作用，并确定Angiomotins是否可以在体内驱动肿瘤发生。鉴于NF2突变涉及广泛的癌症，这些研究将产生广泛的影响，1)阐明细胞调节细胞增殖的分子机制：细胞接触，2)确定Merlin与肿瘤抑制相关的功能，3)确定Hpo/Yap途径的作用，4)验证Angiomotins作为治疗干预开发的新靶点。

DESCRIPTION (provided by applicant): While normal cells possess mechanisms that inhibit proliferation when conditions are inappropriate, tumor cells circumvent these mechanisms and continue proliferating. These regulatory mechanisms are triggered by diverse stimuli such as "cell-cell contact", when cells reach a critical number and density. This "contact- inhibition" oftn becomes dysregulated during tumorigenesis and our long-term goals are to identify and characterize the mechanisms of how cell:cell contact triggers anti-proliferative/growth control signals. A central player in the regulation of these signals is Merlin, the protein product of the NF2 (neurofibromatosis type 2) tumor suppressor gene. Recent studies have indicated the NF2 allele is functionally inactivated in a broad range of tumors. Merlin is localized to regions of cel-cell contacts and a major manifestation of Merlin's loss of function is the development of tumors in vivo and loss of "contact inhibition" of cell proliferation. Merlin has been shown to function a a key regulator of multiple signal transduction pathways including those regulated by small G-proteins and the Hpo/Yap pathway. While these pathways play critical roles in regulation of cell proliferation, organ size control and tissue repair, it is still not clear which of these pathways mediates Merlin's tumor suppressive function/s. We recently identified the Angiomotins, members of the Motin protein family, as Merlin-interacting proteins that localize to tight and adherens junctions. Importantly, we determined that Merlin's ability to regulate mitogenic signaling is mediated through the Angiomotins and that the Angiomotins are required for tumorigenesis in an animal model of NF2. Our working hypotheses are that Merlin functions as a tumor suppressor by regulating signaling pathways that control cellular proliferation through interaction with the Angiomotins and that targeting the Angiomotins will result in inhibition of tumorigenesis. We will test these hypotheses employing cell-based and animal models of NF2 to identify the mechanisms underlying Merlin and Angiomotin-dependent regulation of cell proliferation, establish the roles of the Hpo/Yap pathway and Angiomotin in NF2 and determine whether Angiomotins can drive tumorigenesis in vivo. Given the involvement of NF2 mutations in a broad spectrum of cancers, these studies will have broad impact and 1) elucidate the molecular mechanisms underlying regulation of cellular proliferation by cell:cell contact, 2) determine the functions of Merlin relevant to tumor suppression, 3) establish a role for the Hpo/YAP pathway and 4) validate the Angiomotins as novel targets for development of therapeutic interventions.